The current proposal represents our continued studies of the histogenesis and differentiation lineages underlying the formation of the major forms of human lung cancer. We will focus upon initial findings that the 5' region of the calcitonin gene has a unique hypermethylation pattern in DNA extracted from patients with lung cancer and with lymphomas. Among the spectrum of lung cancers, the hypermethylation pattern is most extensive in classic small cell lung cancer (SCLC) and a less extensive, but abnormal pattern, is also found more frequently in so-called "variant" SCLC cells. Within the spectrum of the major types of human lung cancer, the incidence for the presence of the abnormal methylation pattern parallels that for the distribution of a marker for neuroendocrine differentiation. The present studies are designed to extend our observations regarding the incidence of the abnormal methylation pattern in human cancers, to determine whether the patterns are unique to tumor DNA or might reflect the cell compartments in normally renewing adult tissues from which individual types of lung cancers and/or lymphomas arise, to correlate the degree of hypermethylation with patterns of expression for the CT gene, and to ascertain whether the methylation patterns might serve as markers for refining the diagnostic categories of lung cancer in a clinically significant manner. Techniques to be used in these studies include cell culture, DNA-DNA hybridization, DNA-RNA hybridization, Southern and Northern blotting techniques.